Stimulation of DNA synthesis in murine lymphocytes by the drug swainsonine: immunomodulatory properties.

Swainsonine, an inhibitor of Golgi alpha-mannosidase II, has recently been shown to have potent antimetastatic activity in experimental metastasis assays. In the case of systemic administration, the possible mechanism of action is unknown; the results reported here indicate that it can be explained at least in part by swainsonine stimulation of lymphocyte proliferation. In the present experiments, the standard in vitro mitogenic stimulation assay was used to test the effect of swainsonine on spleen cells. Treatment of spleen cell cultures with the optimum concentrations of the drug enhanced proliferation by 80-146%, as measured by (3H) thymidine incorporation, relative to untreated cultures. Similarly, when spleen cell cultures were prepared from mice maintained on swainsonine-supplemented drinking water, proliferation was stimulated at least 3-fold relative to cultures derived from animals maintained on regular water. The enhanced mitogenesis is apparently not directly related to increased expression of Concanavalin A (Con A) binding sites, since swainsonine induced mitogenesis is not inhibited by alpha-methyl-mannoside in contrast to Con A induced mitogenesis which is completely inhibited. These results suggest that the antimetastatic effect of systemically administered swainsonine is at least in part related to its ability to enhance proliferation of those specific cell populations involved in immune surveillance. This represents the first demonstration of a mechanism of action of swainsonine on the immune system.